Previous in vitro studies using a variety of experimental approaches have established the existence of an inhibitory nervous system in the airways of several species, including man, which is neither adrenergic nor cholinergic. Because the neurotransmitter has not been identified, the system has come to be known as the nonadrenergic inhibitory system (NAIS). Owing to the lack of an in vivo model, the functional significance of the NAIS has not been studied. In addition, little is known about the basic pharmacology of the system or its importance in hyperreactive airways disease. Recently, we have learned that when cats are pretreated with atropine and propranolol, stimulation of the caudal end of the cut cervical vagus nerve reverse in lung resistance induced by a broncho-constricting agent. Thus, the cat can serve as a useful in vivo model for studies of the lung NAIS. We propose to use this model in conjunction with in vitro techniques to (1) detemine the role of the lung NAIS in modulating airway responses to bronchoconstrictive stimuli and to compare NAIS function in isolated tracheobronchial smooth muscle tissues obtained at operation from patients with and without a history of hyperreactive airways disease, (2) obtain pharmacologic evidence which will aid in identifying the neurotransmitter responsible for nonadrenergic bronchodilation with special emphasis on vagal peptides and (3) characterize the basic pharmacologic properties of the lung NAIS particularly with regard to the ability of selected agents to augment or inhibit its smooth muscle relaxing function. By delineating the functional significance of the lung NAIS, this research could provide new insight into the physiologic mechanisms regulating airway caliber and the pathogenetic mechanisms underlying hyperreactive airways disease. In addition, the pharmacologic information derived from these studies could provide a chemical rationale for the synthesis of more effective therapeutic agents for the treatment of hyperreactive airways disease.